Meprobamate, metabolism

Both meprobamate and alcohol are CNS depressants, which appear to have additive effects. There is also some evidence that alcohol may inhibit or increase meprobamate metabolism, depending on whether it is taken acutely or chronically, but the contribution of this to the enhanced CNS depression is uncertain. Meprobamate does not appear to increase blood alcohol levels. ... 

Tsukamoto, H., Yoshimura, H. and Tatsumi, K. (1963) Metabolism of drugs. XXXV. Metabolic fate of meprobamate. (3). A new metabolic pathway of carbamate group - the formation of meprobamate N-glucuronide in animal body. Chemical S[ Pharmaceutical Bulletin, 11, 421. 

Renai function impairment Use with caution to avoid accumulation, since meprobamate is metabolized in the liver and excreted by the kidney. 

Aicohoi Acute ingestion may result in a decreased clearance of meprobamate through inhibition of hepatic metabolic systems enhanced CNS depressant effects may occur. 

Pharmacokinetics Metabolized in liver to meprobamate. Excreted in urine. Half-life 8 hr. 

This difference could be due either to a lack of absorption of sila-meprobamate when given orally or to a different detoxification pathway. Fessenden und Ahlfors, who investigated the metabolic fate72 of 64b, 66b and 71b after peroral application in rats, could show that sila-meprobamate is absorbed from the gastrointestinal tract. After oral application of 66b, 60—90% of the ingested silicon was found in the urine within 3 days. On the basis of spectral evidence, Fessenden postulated the structures 79 and 80 for the isolated metabolic products (Scheme 5) ... 

The major metabolite 79 is analogous to the major detoxification product 81 of meprobamate itself. Metabolism of meprobamate leads to compounds 81,82 and 83 (Scheme 6) ... 

Long term or excessive use of these medications may also cause tolerance and physical dependence.14,31 In particular, carisoprodol should be used cautiously because this drug is metabolized in the body to form meprobamate, which is a controlled substance (see Chapter 1) that has sedative/anxiolytic properties but is not used extensively because it has strong potential for abuse.13,73 Hence, use of cariso-... 

However, most organosilicon compounds are metabolized after ingestion or injection, and their metabolites are eliminated. For example, silameprobamate (27) undergoes to - 1 hydroxylation, following the same pattern as meprobamate itself. The difference in the metabolism of the two compounds is that the silicon compound also undergoes silicon-carbon cleavage to yield a silanol that can be isolated from the urine as a disiloxane (32) see Eq. (1). 

This is a centrally acting skeletal muscle relaxant whose active metabolite is meprobamate. It is metabolized primarily by CYP2C19,... 

Because of its relation to benzodiazepines, dependence on carisoprodol can be a problem. Among patients who had taken carisoprodol for 3 months or more, up to 40% had used it in amounts larger than prescribed, and up to 30% had used it for an effect other than that for which it was prescribed (2). A significant percentage of physicians were unaware of the potential of carisoprodol for abuse and of its metabolism to meprobamate. Patients with carisoprodol withdrawal can present with agitation, restlessness, hallucinations, seizures, anorexia, and vomiting. 

Meprobamate is well absorbed by the gastrointestinal tract and when taken orally, at therapeutic dosing, has a peak serum concentration within 2-3 h. When taken in overdose, absorption can be prolonged (reported up to 13 h) and clinical signs and symptoms may be delayed. Meprobamate is rapidly metabolized in the liver to inactive hydroxy and glucuronide metabolites. 

This sensitivity toward lateral attacks explains the four times shorter duration of action of sila-meprobamate compared to its carbon isostere on a model of tranquiUizing activity in mice (rotarod test, potentiation of hexobarbital-induced sleep, and intraperitoneal injection). " On the other hand, when given orally, sila-meprobamate is practically inactive. One of the first metabolites formed has been characterized as being a di-siloxane (Figure 15.67). For the two phenyl-trimethylsilyl-derived AChE inhibitors, the rather positively charged trimethyl-silyl group mimics the trimethyl-ammonium function present in acetylcholine. Eor these compound metabolic oxidation does not take place on the silicon, but on one of methyl groups (S1-CH3 Si—CH2—OH). ... 

Carbamates - Further studies of the recently marketed tybamate have. been reported. Geller j as placed it between meprobamate and CPZ in its psychopharmacological effectiveness. Although it attenuates punishment discrimination at higher doses than meprobamate, it blocks avoidance responding at doses that do not block escape responses. The absence of withdrawal symptoms, previously observed in the dog, has been demonstrated in man.83 Tybamate is metabolized in the dog and rat principally by conversion of its n-propyl substituent into a 2-hydroxypropyl group.This is accompanied by some N-debutylation. 

Comparative studies with a series of twelve C/Si pairs of the meprobamate/sila-meprobamate type (68a/68b) also revealed, with only a few exceptions, great similarities in the biological properties of the respective C/Si analogues138 (for structurally related silicon compounds see also Reference 142). The C/Si pairs were tested for their acute toxicity, and for sublethal activity the rotating rod test and the extension of hexobarbital sleeping time were used (mice, intraperitoneal administration). In addition, the metabolism of sila-meprobamate (68b) and some of its derivatives was studied139 (for this subject see Section IV). 

In examining the early inflammatory reaction after the implantation of pellets of plastic sponge in the rat, Saxena measured exudate formation and leucocytic infiltration. The cellular infiltration was significandy decreased by the CNS depressants morphine, pentobarbitone, meprobamate and chlorpromazine hydrochloride promethazine hydrochloride is ineffective. The extent to which this may be a direct metabolic effect of the drugs is not clear since the phagocytic activity of circulating leucocytes is decreased by chlorpromazine . 

Van der Kleijn E, Protein binding and lipophilic nature of ataractics of the meprobamate and diazepine group. Arch. Int. Pharmacodyn., 179, 225-250 (1969). NB No references or experimental details given cited in Van der Kleijn E, Kinetics of distribution and metabolism of diazepam and chlordiazepoxide in mice. Arch. Int. Pharmacodyn., 178, 193-215 (1969). 

Misra PS, Lefevre A, Ishii H, Rubin E, Lieber CS. Increase of ethanol, meprobamate and pentobarbital metabolism after chronic edianol administration in man and in rats. Am J Med... 

Examples of other substances which stimulate their own metabolic destruction are chlorcyclizine, probenecid, tolbutamide, aminopyrine, meprobamate, glutethimide, chlorpromazine, chlordiazepoxide, methoxyflurane, 3,4-benzpyrene, and DDT. 

In 1955, meprobamate (Figure 89.4) was introduced as a mild tranquilizer . It gained the epithet Happy Pills and was associated with abuse and habituation. In 1959, the drug was modified with an isopropyl group and marketed as a muscle relaxant, carisoprodol (Soma). Carisoprodol (Figure 89.5) is metabolized to meprobamate. Carisoprodol, like meprobamate, has addictive properties. Carisoprodol has been ranked number 14 of the 20 most abused mood-altering drugs in the USA [9,10]. 

A study of the kinetics of distribution and metabolism of meprobamate, carisoprodol and tybamate was made using mice. The author was able to correlate higher brain levels of the drugs with increased lipid solubility (see also reference 28). ... 

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